PAK1 silencing is synthetic lethal with CDK4/6 inhibition in gastric cancer cells via regulating PDK1 expression
Gastric cancer (GC) is one of the most common malignancies worldwide. The prognosis of GC is unsatisfied owning to widespread metastasis. P21-activated kinase 1 (PAK1), a member of serine/threonine kinases, is associated with the progression of multiple types of human cancers. Here, we demonstrated that CDK4/6 inhibitor reduced GC cell viability and decreased PAK1 expression. Consistently, PAK1 ablation increased GC cell sensitivity exposed to CDK4/6 inhibitor and promoted DNA damage. We also revealed PAK1 depletion notably affected PDK1-AKT pathway, and PDK1 overexpression totally abrogated the effect of PAK1 deletion on DNA damage in GC cells. Additionally, PDK1 overexpression also rescued the increased GC cell sensitivity towards CDK4/6 inhibitor and the cell cycle arrest caused by PAK1 depletion. Our findings, therefore, suggested that PAK1 silencing increased sensitivity to CDK4/6 inhibition in gastric cancer cells via PDK1–AKT pathway. We, therefore, thought PAK1 as a promising therapeutic target for the treatment of CDK4/6 inhibitor-resistant gastric cancer.
KeywordsP21-activated kinase 1 (PAK1) Gastric cancer (GC) PDK1 pathway Proliferation CDK4/6 inhibitor
WS and YQ conceived and designed the experiments, XW and HXW analyzed and interpreted the results of the experiments, and GWH and XH performed the experiments.
Compliance with ethical standards
Conflict of interest
The authors state that there are no conflicts of interest to disclose.
- 6.Pavey S, Zuidervaart W, van Nieuwpoort F, Packer L, Jager M, Gruis N, et al. Increased p21-activated kinase-1 expression is associated with invasive potential in uveal melanoma. Melanoma Res. 2006;16(4):285–96. https://doi.org/10.1097/01.cmr.0000222589.30117.f2.CrossRefPubMedGoogle Scholar
- 12.Li LH, Wu GY, Lu YZ, Chen XH, Liu BY, Zheng MH, et al. p21-activated protein kinase 1 induces the invasion of gastric cancer cells through c-Jun NH2-terminal kinase-mediated activation of matrix metalloproteinase-2. Oncol Rep. 2017;38(1):193–200. https://doi.org/10.3892/or.2017.5643.CrossRefPubMedGoogle Scholar
- 14.Zhou Y, Zhang J, Wang J, Cheng MS, Zhao DM, Li F. Targeting PAK1 with the small molecule drug AK963/40708899 suppresses gastric cancer cell proliferation and invasion by downregulation of PAK1 activity and PAK1-related signaling pathways. Anat Rec. 2019;302(9):1571–9. https://doi.org/10.1002/ar.24095.CrossRefGoogle Scholar
- 15.Fu H, Zhang W, Yuan Q, Niu M, Zhou F, Qiu Q, et al. PAK1 promotes the proliferation and inhibits apoptosis of human spermatogonial stem cells via PDK1/KDR/ZNF367 and ERK1/2 and AKT pathways. Mol Ther Nucleic Acids. 2018;12:769–86. https://doi.org/10.1016/j.omtn.2018.06.006.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Jansen VM, Bhola NE, Bauer JA, Formisano L, Lee KM, Hutchinson KE, et al. Kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer. Cancer Res. 2017;77(9):2488–99. https://doi.org/10.1158/0008-5472.CAN-16-2653.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Symeonidis N, Lambropoulou M, Pavlidis E, Anagnostopoulos C, Tsaroucha A, Kotini A, et al. PAK1 expression in pancreatic cancer: clinicopathological characteristics and prognostic significance. Clin Med Insights Oncol. 2019;13:1179554919831990. https://doi.org/10.1177/1179554919831990.CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Padgaonkar A, Rechkoblit O, Vasquez-Del Carpio R, Pallela V, Venkata Subbaiah D, Cosenza SC, et al. Targeting protein kinase CK2 and CDK4/6 pathways with a multi-kinase inhibitor ON108110 suppresses pro-survival signaling and growth in mantle cell lymphoma and T-acute lymphoblastic leukemia. Oncotarget. 2018;9(102):37753–65. https://doi.org/10.18632/oncotarget.26514.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Cao J, Zhu Z, Wang H, Nichols TC, Lui GYL, Deng S, et al. Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer. Oncogene. 2019;38(21):4125–41. https://doi.org/10.1038/s41388-019-0708-7.CrossRefPubMedGoogle Scholar
- 32.Tempka D, Tokarz P, Chmielewska K, Kluska M, Pietrzak J, Rygielska Z, et al. Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes human lung cancer cells to anticancer drug-induced death by impairing OGG1-dependent base excision repair. Redox Biol. 2018;15:316–26. https://doi.org/10.1016/j.redox.2017.12.017.CrossRefPubMedGoogle Scholar